Yokukansan and treatment-resistant schizophrenia?

I'll freely admit that I'm no expert on yokukansan (YKS), the "traditional Asian herbal medicine" that comprises Atractylodis lanceae Rhizoma, Poria, Cnidii Rhizoma, Uncariae Uncis cum Ramulus, Angelicae Radix, Bupleuri Radix and Glycyrrhizae Radix. 

Yokukansan, in some circles also known as TJ-54, has however cropped up on my autism research radar before as per the very preliminary findings reported by Miyaoka and colleagues [1] (open-access) a few years back suggesting that the herbal combination might "be effective and well tolerated for treatment of severe irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech in patients with PDD-NOS or Asperger’s disorder." Those are the authors' words by the way, not mine.

Today I'm bringing another paper from Tsuyoshi Miyaoka and colleagues [2] (open-access available here) to the blogging table based on a a slightly improved methodological design and covering a different label in the DSM psychiatry 'bible': schizophrenia, and in particular, schizophrenia with a "history of documented treatment-resistant status." This study follows a stream of other peer-reviewed reports from Miyaoka et al on the topic of yokukansan and psychiatry (see here).

The latest paper is open-access but here are a few basics:

• Adult in-patients fulfilling DSM-IV-TR criteria for schizophrenia (N=120) and treatment-resistant status defined as "little or no response to treatment from at least two adequately dosed antipsychotic trials for at least 4 weeks including at least one second-generation antipsychotic (>600 mg/day of chlorpromazine equivalent)" among other things were included for study.
• Based on a "4-week, double-blind, placebo-controlled, fixed-flexible dose trial" participants were either allocated to receive TJ-54 or placebo (although I can't actually find the details of what the placebo consisted of). Baseline and follow-up measures including "psychopathology... assessed using the Positive and Negative Syndrome Scale (PANSS)" were conducted.
• "Existing medications at baseline remained unchanged, whereas initiation of other psychotropic medications was not permitted during the trial." This important point not only means that TJ-54 supplementation was an adjuvant (add-on) treatment for some but also offers some degree of 'stability' insofar as results not being attributable to other interventions being introduced over the study period.
• Results: the authors have tried to cover quite a few bases with their interpretation of the study findings both looking at results from an intention-to-treat (ITT) perspective and a per-protocol set. This means that different numbers of trial completers (or non-completers) are included in their analyses. The headline result: "TJ-54 showed a tendency of being superior to placebo in reduction total, positive, and general PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant." So after 4-weeks in general, there were potential changes following the use of TJ-54 but one can't rule out these being just due to chance.
• The devil however, might be in the detail when it comes to results. So: "compared to the placebo group, TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores for lack of spontaneity and flow of conversation, tension, and poor impulse control." Further: "When TJ-54 was combined with antipsychotics, the therapeutic benefits were significantly enhanced" highlighting how once again (see here) adjuvant therapy alongside antipsychotics might be the way forward for the management of some schizophrenia and beyond.
• Just as important for the discussions about possible effectiveness of TJ-54 are the author comments about side-effects: "Overall, TJ-54 was well tolerated with no severe or serious adverse effects." First, do no harm and all that.

The authors not only call for further research on TJ-54 and schizophrenia but are actually doing it themselves as per the comment: "The 4-week treatment duration was too short, which might have prevented us from exploring the efficacy of TKS [or should this be YKS?]. Therefore, now, we are conducting 12-week trial." Talk about getting on and doing it yourself eh?

I'm rather interested in these and other results [3] and their potential indications for at least some schizophrenia under certain circumstances. Treatment-resistant schizophrenia is a significant issue for a proportion of those diagnosed and can quite severely impact on quality of life for those in such a position [4]. Finding novel ways and means to overcome the various issues that a diagnosis of schizophrenia can potentially bring in that scenario is an important goal for psychiatry.

In terms of the possible explanations for the effects of TJ-54, well, once again we're left in head-scratching and speculation mode based on the current and other observations. Chuan-Hsun Yu and colleagues [5] (open-access) talk about some of the potential pharmacological implications of YKS supplementation focused quite a bit on the "antipsychotic implications of yokukansan." I'd be minded to suggest that alongside just monitoring potential effectiveness of YKS, science should really be doing quite a bit more on the biological processes potentially affected by supplementation, reiterating that YKS is a mixture and might have one than one biological effect.

To close: How to Swear Like a Brit. Not such a load of b******s.

----------

[1] Miyaoka T. et al. Yokukansan (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger's disorder: a 12-week prospective, open-label study. BMC Psychiatry. 2012 Nov 29;12:215.

[2] Miyaoka T. et al. Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, multicenter, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med. 2015;2015:201592.

[3] Miyaoka T. et al. Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled trial (a Positive and Negative Syndrome Scale, five-factor analysis). Psychopharmacology (Berl). 2015 Jan;232(1):155-64.

[4] Englisch S. & Zink M. Treatment-resistant Schizophrenia: Evidence-based Strategies. Mens Sana Monogr. 2012 Jan;10(1):20-32.

[5] Yu CH. et al. Yokukansan and its ingredients as possible treatment options for schizophrenia. Neuropsychiatr Dis Treat. 2014 Sep 1;10:1629-34.

----------

Miyaoka T, Furuya M, Horiguchi J, Wake R, Hashioka S, Thoyama M, Murotani K, Mori N, Minabe Y, Iyo M, Ueno S, Ezoe S, Hoshino S, & Seno H (2015). Efficacy and safety of yokukansan in treatment-resistant schizophrenia: a randomized, multicenter, double-blind, placebo-controlled trial. Evidence-based complementary and alternative medicine : eCAM, 2015 PMID: 25954314